Conformationally constrained analogues of diacylglycerol (DAG).: Part 19:: Asymmetric syntheses of (3R)- and (3S)-3-hydroxy-4,4-disubstituted heptono-1,4-lactones as protein kinase C (PK-C) ligands with increased hydrophilicity

The stereospecific introduction of (R)- and (S)-OH groups at position C-3 of two diacylglycerol gamma-lactones (DAG-lactones) previously identified as strong protein kinase C (PK-C) ligands is presented. The compounds were designed to investigate whether the extra OH group in a specific orientation could establish an additional hydrogen bond with the C1 domain of PK-C, thus providing a DAG analogue with reduced lipophilicity. The OH groups were introduced following two different diastereoselective multistep syntheses starting from diacetone-D-glucose. The PK-C binding affinities for the new compounds were weaker in comparison to those of the parent compounds, suggesting that the extra OH does not engage efficiently in hydrogen bonding at the receptor. (C) 2002 Elsevier Science Ltd. All rights reserved.